Process for the preparation of trisubstituted ureas

ABSTRACT

The present invention provides a process for preparing a trisubstituted urea of the general formula:

United States Patent 1 Hearsey 1 Oet.7,1975

[75] Inventor: Colin John Hearsey, Surbiton,

England [73] Assignee: Quimco GmbI-I, Zuerich,

Switzerland [22] Filed: Mar. 30, I973 [21] Appl. No.: 346,480

[30] Foreign Application Priority Data Apr. 5, 1972 United Kingdom15677/72 Aprv I8. 1972 United Kingdom 17872/72 May 5, 1972 UnitedKingdom 21063/72 [52] US. Cl... 260/553 A; 260/247.2 A; 260/287 R;260/293.86; 260/326.l l; 260/326.4

[51] Int. Cl. C07C 127/19 [58] Field of Search 260/555 R, 555 A, 247.2

[56] References Cited UNITED STATES PATENTS 2,683,696 7/1954 Muller260/553 A $119,682 7/1954 Martin 260/553 A FOREIGN PATENTS ORAPPLICATIONS 203.940 3/1955 Australia 260/553 A Primary ExaminerRobertGerstl Assistant ExuminerPaul J. Killos Atlorney, Agent, or Firm-ClelleW. Upchurch [57] ABSTRACT The present invention provides a process forpreparing a trisubstituted urea of the general formula:

in which R is a substituted or unsubstituted mono-, dior polyvalentaromatic radical, R is a substituted or unsubstituted monovalentaliphatic or aromatic radical and R" is a substituted or unsubstitutedmonovalent aliphatic radical or R and R together represent a substitutedor unsubstituted divalent radical in which at least one of the twocarbon atoms adjoining the nitrogen atom of the urea is aliphatic, and nis an integer, wherein an aromatic nitrocompound of the general formula:R(NO or an aromatic nitrosocompound of the general formula: R(NO), isallowed to react with a secondary ammonium N,N-disubstitutedthiolcarbamate of the general formula:

R'R"NCOS'.N I-I RR or with a mixture of a secondary amine of the generalformula: R'R"NH and carbon monoxide and sulphur, carbon monoxide andhydrogen sulphide, or carbonyl sulphide, or with a mixture of asecondary ammonium sulphide or hydrosulphide of the general formula:

3 Claims, No Drawings PROCESS FOR THE PREPARATION OF TRISUBSTITUTEDUREAS I This invention relates to' the preparation of trisubstitutedureas from aromatic nitrocompounds or from aromatic nitrosocompounds.The products have several important applications, particularlyagricultural chemicals and as intermediates in the synthesis of otherimportant chemicals, including carbamates and isocyanates.

At the present time, aromatic trisubstituted ureas are most frequentlyprepared by reaction of an aromatic isocyanate with a secondary amine.The isocyanate will normally have been prepared by the; reaction ofphosgene with the corresponding primary amine, which is in turn likelyto have been prepared by reduction of the corresponding nitrocompound.There are several undesirable features in this conventional method, notleast of which are the toxicity and corrosive nature of phosgene and theformation of hydrogen chloride as byproduct. Furthermore, certainaromatic amines are known to have harmful physiological properties andsome are also prone to aerial oxidation in storage.

It has now. been found that trisubstituted ureas may readily be preparedin one step from aromatic nitrocompounds or nitrosocompounds. z

Thus, according to the present invention, there is provided a processfor preparing a trisubstituted urea of the generalformula:

,mula:

V or an aromatic nitrosocompound of the general formula:

is allowed to react with a secondary ammonium N,N- disubstitutedthiolcarbamate of the general formula:

or with a mixture of a secondary amine of the general formula:

R'RNH v and carbon monoxide and sulphur, carbon monoxide and hydrogensulphide, or carbonyl sulphide, or with a mixture of a secondaryammonium sulphide or hydrosulphide of the general formula:

and carbon monoxide.

Typical but not limiting substituents in R are alkyl,

alkoxy. heterocyclic, halogen; typical not limiting dimethylammoniumunder the same conditions. In general, the faster is the substituents inR are alkyl, aryl and heterocyclic; and typical but not limitingsubstituents in R are aryl and heterocyclic.

Typical but not limiting secondary amines in which R and R togetherrepresent a divalent radical in which at least one of the twocarbon-atoms adjoining the nitrogen atom is aliphatic are pyrrolidine,morpholine, piperidine and indoline.

It is to be understood that included in the definition of R above areheterocyclic radicals of aromatic nature.

When the starting material is R(NO it is believed that the presentinvention maybe represented in genera] by the following equations:

Examples of trisubstituted ureas which may be prepared by the process ofthepresent invention are 1,1- d-imethyl-S-phenylurea,1-m-chlorophenyl-3,3- dimethylurea, l ,1-dimethyl-3-( 1 -naphthyl )urea,1,1- dimethyl-3-( 5-quinolyl )urea, 1, l -diallyl-3-m-tolylurea, 1,1l,4-butylene)-3-m-chlorophenylurea, 1,1-dimethyl-3-p-tolylurea, I1,1-dimethyl-3-pmorpholinophenylurea, l-,1'-(2,4-tolylene)-bis-3,3-dimethylurea, 1,1 '-(methylenedi-p-phenylene )-bis-3,3- dimethylurea,1,1 '-(ethylenedi-p-phenylene )-bis-3,3- diethylurea.

The reaction temperature is normally selected within the range 200C andthe reaction is normally performed in an inert solvent. Typical of thesolvents which may be used are benzene, toluene, chlorobenzene, xyleneand o-dichlorobenzene.

In general, the highest yields are obtained when an aromaticnitrocompound is allowed to react with a secondary ammoniumN,N-disubstituted thiolcarbamate. The latter reactant may convenientlybe prepared and purified by the method described in a co-pending patentapplication Ser. No. 312,750 filed Feb. 6, 1972 now US. Pat. No.3,865,875 by allowing the selected secondary amine in a suitable solventto react with sulphur and carbon monoxide at a pressure between 5 and 60atmospheres and at a temperature between 40C and C and by distilling thereaction products to obtain as distillate a purified mixture of reactantplus solvent.

Complete conversion of one equivalent of nitrocompound is achieved, onlywhen a minimum of three equivalents of thiolcarbamate salt is allowed toreact with it. The rate of conversion is dependent on the nature of thenitrocompound. For example, the reaction of m-chloronitrobenzene withdimethylammonium N,N-dimethylthiolcarbamate in chlorobenzene underreflux conditions-is virtually complete within 3 hours, whereas nodetectable reaction takes place within 5 hours betweenp-dimethylaminonitrobenzene and N,N-dimethylthiolcarbamate 7 rate ofconversion, the higher is the yield.

The trisubstituted ureas formed by practising the present invention maybe isolated by any one of several methods. In one of these the reactionproducts are distilled to remove volatiles and the residue is extractedwith warm methanol. The methanol is then filtered to remove theinsoluble sulphur and the methanol is distilled from the filtrate. Theresidue is extracted with refluxing benzene and filtered hot. Theresulting solution is then cooled to give the required product as aprecipi tate.

Besides being important end-products, particularly as agriculturalchemicals, trisubstituted ureas may readily be converted in a singlestep into isocyanatcs or carbamates by the methods described in twoco-pending patent applications Ser. No. 258,308 filed 5/31/72 and Ser.No. 312,752 filed 12/6/72 now US. Pat. No. 3,873,553. Thus the presentinvention facilitates the preparation of a range of important materialswhose manufacture conventionally involves the use of phosgene and theevolution of hydrogen chloride as a byproduct. The by-products resultingfrom the practice of the present invention are carbon dioxide, sulphurand secondary amine (plus water in two of the less importantmodifications), of which the sulphur and the secondary amine may berecycled as such. The sulphur is recovered quantitatively at 100%conversion of starting material and at conversions of less than 100% theyield of sulphur may be used to estimate the conversion.

The present invention avoids the necessity to use aromatic amines asintermediates in the preparation of the title compounds, and also in thepreparation of corresponding isocyanatcs and carbamates. This is animportant advantage since several aromatic amines, such asl-naphthylamine, have been shown to possess pronounced carcinogenicactivity.

The process of the present invention is, in effect, a carbonylation of anitroor nitrosocompound. Many patents have been granted which relate tocarbonylation reactions leading directly to carbamates or isocyanates.However, these methods invariably suffer from the disadvantage ofrequiring an expensive transitional metal catalyst, the recovery ofwhich presents problems, and further of requiring, especially in themost high-yielding processes, the maintenance of a high carbon monoxidepressure for extended periods of time. Many of the best carbonylationprocesses using transition metal catalysts give carbamates rather thanisocyanatcs, and the conversion of carbamates to isocyanates is known tobe an unsatisfactory procedure. It follows that the present inventionpossesses several important advantages in terms both of cost and ofversatility over carbonylation processes which use transition metalcatalysts.

Certain substituents, such as p-chloro chloromethyl and amino, inaromatic nitrocompounds are themselves reactive in the conditions of thepresent invention, and in these cases separate reactions proceed atsites other than the nitro group, thereby altering the constitution ofthe aromatic radical. If it is required to prepare trisubstituted areaswhich possess oand/or p-chloro substituents in the aromatic radical. itis possible to insert these substituents, using the method described ina British Provisional Application No. ()6494/73, by chlorination of thearomatic radical after conversion of the corresponding nitrocompound tothe trisubstituted urea.

The following examples are given for the purpose of illustrating thepresent invention.

EXAMPLE 1 Nitrobcnzene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (33 g.) in chlorobenzene (42g.) for 5 hours under reflux. At the end of this period, the volatiles,including some unreacted nitrobenzene, were distilled off and the residue was extracted with hot methanol. After filtration to remove sulphur3.6 g., 92% of theoretical the methanol was distilled off and theresidue was dissolved in hot benzene and allowed to cool to give aprecipitate of l,l-dimethyl-3-phenylurea (4.0 g.; melting point 125128C)v A further 1.2 g. of product was obtained after the addition of60-80 petroleum ether and this was recrystallised from benzene to givean additional 0.8 g. of 1,l-dimethyl-3-phenylurea, bringing the totalyield to 86% related to a conversion of 92%.

EXAMPLE 2 m-Nitrotoluene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (29 g.) in chlorobenzene (36g.) for 17 hours under reflux. At the end of this period, the volatileswere distilled off and the residue was extracted with hot methanol.After filtration to remove sulphur (3.4 g., 97% of theoretical), themethanol was distilled off and the residue was dissolved in hot benzeneand allowed to cool to give a precipitate of 1,l-dimethyl-3-m-tolylurea(3.2 g.; melting point 124- 127C). A further 1.5 g. was obtained afterthe addition of 6080 petroleum ether, bringing the total yield to 74%related to a conversion of 97%.

EXAMPLE 3 m-Chloronitrobenzene 12.8 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (66 g.) in chlorobenzene (84g.) for 4 /2 hours under reflux. At the end of this period, thevolatiles were distilled off and the residue was extracted with hotmethanol. After filtration to remove sulphur (7.8 g., 100% oftheoretical), the methanol was distilled off and the residue wasdissolved in hot benzene. Petroleum ether (6080) was added and thesolution was cooled to give a precipitate ofl-m-chlorophenyl-3,3-dimethy1urea 14.4 g.; melting point 138 142C) in89% yield related to a conversion of 100%.

EXAMPLE 4 m-Chloronitrobenzene (3.0 g.) was allowed to react withdiethylammonium N,N-diethylthiolcarbamate (20 g.) in chlorobenzene (20g.) for 5 hours under reflux. At the end of this period, the volatileswere distilled off and the residue was extracted with hot methanol.After filtration to remove sulphur (1.4 g., 78% of theoretical), themethanol was distilled off and the residue was extracted with hotbenzene and filtered hot. The benzene was then distilled from thefiltrate and the residue was crystallised from 60-80 petroleum ether togive 1- m-chlorophenyl-3,3-diethylurea (2.2 g; melting point 81 82C) inyield related to a conversion of EXAMPLE 5 Nitrobenzene (5.0 g.) wasallowed to react with dimethylammonium N,N-dimethylthiolcarbamate (18g.) in chlorobenzene (24 g.) for 6 hours under reflux.

At the end of this period, the reaction products were separatedaccording to the method described in Example 1 to give sulphur (2.6 g.,67% of theoretical) and l,l-dimethyl-3-phenylurea (3.8 g.) in 85% yieldrelate to a conversion of 67%.

EXAMPLE 6 Nitrobenzene (5.5 g.) .was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (40 g.) in o-dichlorobenzene(47 g.) for 14 /2 hours under reflux. At the end of this period, thereaction products were separated according to the method of Example 1 togive sulphur (4.3 g., 100% of theoretical) and 1,1-dimethyl-3-phenylurea (6.1 g.) in 84% yield related to a conversion of100%.

EXAMPLE 7 Nitrosobenzene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (50 g.) in o-dichlorobenzene100 g.) for 7 hours under reflux. At the end of this period, thevolatiles were distilled off and the residue was extracted with hotmetha- EXAMPLE 8 A /z-litre capacity autoclave was charged withnitrobenzene (50.0 g.), sulphur (16 g.), dimethylamine (45 g. benzene(75 g.) and carbon monoxide to a pressure of 40 atmospheres. Thecontents of the autoclave were then heated to 110C and retained withinthe range 1 10C 140C with stirring for 2 hours. The pressure of carbonmonoxide was renewed to 40 atmospheres at intervals as required bypassing in additional carbon monoxide. At the end of this period, theautoclave was allowed to cool below 70C and the contents were removedand distilled to separate the volatiles. The latter included 10.3 g. ofnitrobenzene, indicating a conversion of 79%. The residue was extractedwith hot methanol and filtered to remove sulphur. The methanol was thendistilled from the filtrate and the residue was dissolved in hotbenzene. Petroleum ether (60-80) was added and the mixture was cooled togive a precipitate of crude l,l-dimethyl-3-phenylurea (35.3 g.).Recrystallisation of this product from water gave 27.6 g. ofl,l-dimethyl-3-phenylurea (melting point 127 131C), representing a yieldof 52% related to a conversion of 79%.

EXAMPLE 9 A /z-litre autoclave was charged with nitrobenzene (30.0 g.),dimethylammonium sulphide (40 g.), benzene (60 g.) and carbon monoxideto a pressure of 50 atmospheres. The temperature of the autoclave wasraised to 1 10C and its contents were maintained at this temperaturewith stirring for 2 /2 hours. The pressure was renewed to 50 atmospheresat intervals as required by passing in more carbon monoxide. Thecontents of the autoclave were then allowed to cool below 70C beforebeing removed and distilled to separate the volatiles, which includedunreacted nitrobenzene. The residue, weighing 16 g., was recrystallisedfrom a mixture of benzene and 60-80 petroleum ether to give 1,1-dimethyl-3-phenylurea 12.3 g.).

EXAMPLE 10 o-Nitrotoluene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (29 g.) in chlorobenzene (36g.) for 17 hours under reflux. At the end of this period, the volatileswere distilled off and the residue was extracted with hot methanol.After filtration to remove sulphur (3.3. g., 94% of theoretical), themethanol was distilled off and the residue was dissolved in hot benzeneand allowed to cool to give a precipitate of '1,l-dimethyl-3-o-tolylurea(4.1 g.; melting point 139 143C). A further 1.0 g. of product was Iobtained after the addition of a small amount of 60-80 petroleum etherand this was recrystallised from benzene to give an additional 0.7 g. of1,1-dimethyl-3-otolylurea, bringing the total yield to 79% related to aconversion of 94%.

EXAMPLE 1 1 p-Nitrotoluene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (29 g.) in chlorobenzene (36g.) for 16 hours under reflux. At the end of this period, the reactionproducts were separated according to the method of Example 10 to givesulphur (1.8 g., 51% of theoretical) and 1,l-dimethyl-3-p-tolylurea (2.7g.; melting point 154 157C) in 81% yield related to a conversion of 51%.

EXAMPLE 12 2,4-Dinitrotoluene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (66 g.) in chlorobenzene (84g.) for 17 hours under reflux. At the end of this period, the reactionproducts were separated according to the method of Example 10 to givesulphur (4.9 g., 93% of theoretical) and 6.5 g. of a product which aftertwo further recrystallisations from benzene gave 1 ,1 2,4-tolylene)bis-3 3- dimethylurea (3.4 g.; melting point 182 185C) in 51% yieldrelated to a conversion of 93%.

EXAMPLE 1 3 l-Nitronaphthalene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (22 g.) in chlorobenzene (28g.) for 14 /2 hours under reflux. At the end of this period, thereaction products were separated according to the method of Example 10to give sulphur (2.8 g., of theoretical) and 1,1- dimethyl-3-(l-naphthyl)urea (3.1 g.; melting point 164 168C) in 50% yield related toa conversion of 100%.

EXAMPLE 14 S-Nitroquinoline (4.3 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (33 g.) in chlorobenzene (43g.) for 17 hours under reflux. At the end of this period, the reactionproducts were separated according to the method of Example 10 to givesulphur (2.1 g., 89%- of theoretical) and crude 1,1-dimethyl-3-(5-quinolyl)urea (3.3 g. Further recrystallisation from amixture of methanol and water gave 2.2

g. of l,1-dimethyl-3-(5-quinolyl)urea with melting point 188 193C,representing a 47% yield related to a conversion of 89%.

EXAMPLE l p-Morpholinonitrobenzene (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (26 g.) in chlorobenzene (34g.) for 1 8 /2 hours under reflux. At the end of this period, thereaction products were separated according to the method of Example togive sulphur (0.6 g., 30% of theoretical) and 1.0 g. of crude product,which on further recrystallisation from benzene gavel,l-dimethyl-3-pmorpholinophenylurea (0.6 g.; melting point 199 204C) in33% yield related to a conversion of 30%.

EXAMPLE l6 2-Nitrobiphenyl (5.0 g.) was allowed to react withdimethylammonium N,N-dimethylthiolcarbamate (33 g.) in chlorobenzene (l17 g.) for l6 hours under reflux. At the end of this period, thevolatiles were distilled off and the residue was extracted with hotmethanol. After filtration to remove sulphur (1.8 g.; 75% oftheoretical), the methanol was distilled off and the residue wasextracted with hot benzene and filtered hot. Petroleum ether (40-60) wasadded to the filtrate, which was then cooled to give 3.4 g. of crudeproduct. Recrystallisation from a mixture of benzene and petroleum ethergave l-(2-biphenyl)-3,3-dimethylurea (2.3 g.; melting point 89 93C) in51% yield related to a conversion of 75%.

What is claimed is: 1. A process for preparing a trisubstituted urea ofthe formula:

mula:

is reacted with a secondary ammonium l\l,N- disubstituted thiolcarbamateof the formula:

RR"NCOS.N H RR.

2. A process according to claim 1 in which the reaction is performed inan inert solvent.

3. A process according to claim 1 in which the reac tion is performed ata temperature within the range

1. A PROCESS FOR PREPARING A TRISUSTITUTED UREA OF THE FORMULA:
 2. Aprocess according to claim 1 in which the reaction is performed in aninert solvent.
 3. A process according to claim 1 in which the reactionis performed at a temperature within the range 80* - 200*C.